The efficacy of any cancer chemotherapy is limited by the sensitivity of specific cancers to a particular treatment. Even when a cancer is responsive to a particular chemotherapy, acute and chronic toxic effects associated with the chemotherapy often force a reduction in dose or discontinuation of treatment altogether. One approach to treatment of non-responsive cancers or to overcome dose-limiting toxicity is to combine agents which act via different mechanisms of action. Although some advantageous chemotherapy combinations have been discovered, the identification of combinations of agents that demonstrate improved efficacy at a particular cancer or that are better tolerated by the patient remains essentially empirical.
Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase implicated in various signal transduction networks known to regulate a variety of cell functions. The role of GSK3β in cancer treatment is unclear. Rapamycin, for example, is reported to dramatically potentiate the effects of paclitaxel, vinorelbine, and carboplatin, but not the effects of doxorubicin or gemcitabine, in breast cancer cells by activation of GSK3β. This potentiation was inhibited by the well-known GSK3β inhibitors lithium chloride, SB216763, and SB415286. (Dong, et al., Cancer Research, 65(5), 1961-1972 (2005)) In contrast, lithium chloride and SB216763, inhibitors of GSK3β, have been shown to dramatically potentiate the anti-tumor efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in both p53 positive and p53 negative prostate cancer cells at sub-toxic concentrations. (Liao, et al., Molecular Cancer Therapeutics, 2, 1215-1222 (2003)) Similarly, lithium chloride was shown to sensitize tumor cells to tumor necrosis factor (TNF) in human rhabdomyosarcoma cells and murine fibrosarcoma cells, but GSK3β inhibitors Ro31-8220, valproic acid, and indirubin-3′-monoxime failed to potentiate the same effect. (Schoette, et al., The Journal of Biological Chemistry, 276(28), 25939-25945 (2001)) Finally, GSK3β inhibitors lithium chloride and LY2119301 are reported to potentiate the effects of adriamycin, etoposide, and 5-fluorouracil in p53 positive colon cancer cells, but neither SB216763 nor SB415286 potentiated the effects of any agent tested, and all of the GSK3β inhibitors tested failed to demonstrate the desired potentiation in p53 negative colon cell lines. (Tan, et al., Cancer Research, 65(19), 9012-9020 (2005)).
There is a need for specific combinations of agents that exhibit improved efficacy in the treatment of a cancer patient with a particular cancer, or that allows a cancer patient to better tolerate chemotherapy. The GSK3β inhibitor 7-(2,5-dihydro-4-imidazo[1,2-a]-pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)pyrrolo[3,2,1-jk][1,4]benzodiazepine potentiates the effects of certain chemotherapeutic agents at particular cancers.